Functional characterization of an orphan nuclear receptor, Rev-ErbAa, in chondrocytes and its potential role in steoarthritis

Objective. To evaluate the expression and function of the orphan nuclear receptor Rev-ErbA alpha in articular cartilage and to investigate its role in osteoarthritis (OA). Methods. Expression of Rev-ErbA alpha was analyzed at both the messenger RNA and protein levels in human and bovine articular cartilage and chondrocytes by real-time polymerase chain reaction (TaqMan) and immunocytochemical techniques. The effects of cartilage catabolic and anabolic agents on the expression of Rev-ErbA alpha were evaluated by TaqMan analysis. Overexpression was achieved by either adenoviral transduction or treatment with a peroxisome proliferator-activated receptor alpha agonist, whereas expression was suppressed by antisense oligonucleotides. Results. Among the 48 known nuclear receptors, Rev-ErbA alpha was found to be the most highly expressed in OA cartilage. It is known to function as a transcription repressor. Treatment of articular chondrocytes with known catabolic agents resulted in the induction of Rev-ErbA alpha, whereas stimulation with anabolic agents led to a decrease in expression. Overexpression of the nuclear receptor was associated with an increase in the expression of matrix-degrading enzymes such as matrix metalloproteinase 13 and aggrecanase. In contrast, a decrease in Rev-ErbA alpha expression led to a concomitant reduction in the activity of matrix-degrading enzymes. Conclusion. This study is the first to demonstrate that Rev-ErbA alpha is highly expressed in OA articular chondrocytes and that its expression is modulated by known cartilage catabolic and anabolic stimuli. We also demonstrated that modulation of Rev-ErbA alpha expression in chondrocytes may be a novel means of regulating the expression and production of multiple matrix-degrading enzymes. These observations suggest that Rev-ErbA alpha may be a novel therapeutic target for OA.